Project Term
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Project Summary
The identification of critical therapeutic targets in myeloproliferative neoplasm (MPN) cells will have a significant impact on the development of much needed treatments for the 300,000 MPN patients in the U.S. Deregulated activity of a protein called JAK2 is an important factor that contributes to MPN formation, but currently approved drugs targeting JAK2 have had limited success, as disease-driving cells persistently survive therapy, and thus these drugs can not readily induce remission in patients. After four decades of the identification of the importance of a protein called RAS in cancer, which is also involved in the cancer causing signaling of JAK2 in MPN, an innovative drug has just been developed (in 2024) to directly block RAS activity. This proposal will investigate the potential this exciting new drug may have in novel therapeutic approaches to improve the lives and the long term health and outcomes of MPN patients.
Lay Abstract
Myeloproliferative neoplasms (MPNs) are blood cancers that affect over 300,000 people in the U.S. MPN patients are at elevated risk of death due to blood clotting complications, bone marrow failure, and the development of an incurable leukemia. A curative stem cell transplant is rarely an option for patients. While aberrant activity of a protein called JAK2 drives MPN formation and anti-JAK2 drugs make patients feel better, these drugs cannot readily induce remission, and this inherent ineffectiveness remains a major bottleneck of successful therapy. Ongoing studies indicate certain drugs (e.g., inhibitors of BCL2 proteins that keep cancer cells alive) in combination with JAK2 inhibitors can improve patient responses, but no combination has been identified that readily impedes disease to induce remission. Previous studies have shown that signaling by RAS proteins can make cells resist the growth inhibitory effects of JAK2 inhibitors. Researchers have attempted to inhibit RAS ever since the identification of its role in cancer over 40 years ago. Finally in 2024 a drug that can inhibit RAS was reported and has shown amazing results in pre-clinical studies of solid tumors. Importantly, this drug has little effect on healthy cells in mice and early clinical trial data available to date indicate it has a strong safety profile in humans. Excitingly, our current studies indicate RAS inhibition by this drug may be a novel approach to improve MPN therapies. These studies indicate this inhibitor antagonizes the growth of primary cells from patients and disease development in an MPN mouse model. The combination of JAK2 and RAS inhibition further enhances the anti-MPN effects compared to either drug alone in these studies. Our studies also show that RAS inhibition along with a drug called navitoclax, which inhibits BCL2 proteins that impede cell death, together lead to enhanced MPN cell killing. The objective of this proposal is to develop pre-clinical support indicating the direct targeting of RAS has potential to contribute to novel effective therapeutic strategies for MPN. We will determine the extent to which RAS inhibition can improve the MPN therapeutic response to JAK2 inhibition as well as in combination with BCL2 inhibition in cellular and in vivo therapeutic mouse MPN models. Supported by strong preliminary data, our studies are innovative because they will utilize an exciting new drug to inhibit a critical protein in cancer called RAS, will be the first to assess direct inhibition of RAS in MPN – which would also be the first assessment in blood cancer as studies with this drug to date have focused on solid tumors – and our assessment of combining RAS and BCL2 inhibition is a novel approach to inhibit JAK2 induced signals while circumventing the challenges of using JAK2 inhibitors. Our studies could support rapid clinical testing and development of effective therapies to improve the lives and reduce deaths of those who suffer with MPN.
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